New Research

Chemistry–Biology Combined Research

Chemical Approach to DNA Damage and Repair

We are studying nucleic acids (DNA and RNA), as well as proteins that interact with them, from a chemical point of view.

DNA is an organic compound that has a string of carbon atoms, and undergoes various chemical reactions (DNA damage) within a living organism. Consequently, alteration of the chemical structure of DNA, i.e. genetic information, induces mutagenesis, which leads to carcinogenesis and cell death. Although DNA is always damaged, all living organisms possess DNA repair systems, and thus genetic integrity is maintained. We have developed methods for the chemical synthesis of damaged DNA fragments, and using them, mechanisms of DNA recognition and catalytic reactions by the repair proteins have been investigated. Here, we introduce recently published studies on DNA containing the (6–4) photoproduct, which is produced by ultraviolet light and is repaired by the nucleotide excision repair (NER) pathway.

We have been studying how the UV-DDB protein that initially binds to the damage site in the NER pathway finds the target. We presumed that the (6–4) photoproduct makes the DNA helix flexible (Fig. A), and the protein may recognize this physical property. We synthesized modified DNA in which a chemical reaction occurs when the helix is bent, and demonstrated the dynamic structural change.

Xeroderma pigmentosum is hereditary disease whose patients lack the NER ability and are likely to develop skin cancer upon exposure to sunlight. Since early diagnosis of this disease is important, we developed a sensor that detects the NER ability of cells. It was a circular DNA containing the (6–4) photoproduct at a single site, and a fluorophore–quencher pair was attached to it. When normal cells were transfected with this molecule, fluorescence was observed in the cells (Fig. B), but no fluorescence was detected for NER-deficient cells. We are now improving it toward clinical application.